Department of Biology, Southern University of Science and Technology, Shenzhen 518055, China.
Shenzhen Key Laboratory of Cell Microenvironment, Southern University of Science and Technology, Shenzhen 518055, China.
Proc Natl Acad Sci U S A. 2017 Aug 29;114(35):9349-9354. doi: 10.1073/pnas.1703064114. Epub 2017 Jul 24.
Kindlins and talins are integrin-binding proteins that are critically involved in integrin activation, an essential process for many fundamental cellular activities including cell-matrix adhesion, migration, and proliferation. As FERM-domain-containing proteins, talins and kindlins, respectively, bind different regions of β-integrin cytoplasmic tails. However, compared with the extensively studied talin, little is known about how kindlins specifically interact with integrins and synergistically enhance their activation by talins. Here, we determined crystal structures of kindlin2 in the apo-form and the β1- and β3-integrin bound forms. The apo-structure shows an overall architecture distinct from talins. The complex structures reveal a unique integrin recognition mode of kindlins, which combines two binding motifs to provide specificity that is essential for integrin activation and signaling. Strikingly, our structures uncover an unexpected dimer formation of kindlins. Interrupting dimer formation impairs kindlin-mediated integrin activation. Collectively, the structural, biochemical, and cellular results provide mechanistic explanations that account for the effects of kindlins on integrin activation as well as for how kindlin mutations found in patients with Kindler syndrome and leukocyte-adhesion deficiency may impact integrin-mediated processes.
衔接蛋白和纽带蛋白是整合素结合蛋白，它们在整合素激活中起着至关重要的作用，整合素激活是许多基本细胞活动（包括细胞-基质黏附、迁移和增殖）所必需的过程。作为 FERM 结构域蛋白，纽带蛋白和衔接蛋白分别结合β整合素胞质尾部的不同区域。然而，与广泛研究的衔接蛋白相比，关于衔接蛋白如何特异性地与整合素相互作用并协同增强其激活的机制，人们知之甚少。在这里，我们确定了衔接蛋白 2 在apo 形式和β1 和β3 整合素结合形式下的晶体结构。apo 结构显示出与衔接蛋白不同的整体结构。复合物结构揭示了衔接蛋白独特的整合素识别模式，它结合了两个结合基序，提供了对整合素激活和信号转导至关重要的特异性。引人注目的是，我们的结构揭示了衔接蛋白的一种意想不到的二聚体形成。中断二聚体形成会损害衔接蛋白介导的整合素激活。总之，结构、生化和细胞结果提供了机制解释，解释了衔接蛋白对整合素激活的影响，以及在 Kindler 综合征和白细胞黏附缺陷患者中发现的衔接蛋白突变如何影响整合素介导的过程。
